Transplant International

REVIEW

Optimized donor management and organ

preservation before kidney transplantation
€mer, Urs Benck& Peter Schnu
Heiko M. Mundt, Benito A. Yard, Bernhard K. Kra € lle

5th Department of Medicine SUMMARY

(Nephrology/Endocrinology/
Rheumatology), Medical Faculty
Mannheim of the University of
Heidelberg, University Hospital
Mannheim, Mannheim, Germany
Correspondence
Heiko M. Mundt MD, Theodor-
Kutzer-Ufer 1-3, 68167 Mannheim,
Germany.
Tel.: 0049 6213835172;
fax: 0049 6213833804;
e-mail: heiko.mundt@umm.de
Kidney transplantation is a major medical improvement for patients with
end-stage renal disease, but organ shortage limits its widespread use. As
a consequence, the proportion of grafts procured from extended criteria
donors (ECD) has increased considerably, but this comes along with
increased rates of delayed graft function (DGF) and a higher incidence
of immune-mediated rejection that limits organ and patient survival.
Furthermore, most grafts are derived from brain dead organ donors, but
the unphysiological state of brain death is associated with significant
metabolic, hemodynamic, and pro-inflammatory changes, which further
compromise patient and graft survival. Thus, donor interventions to
preserve graft quality are fundamental to improve long-term transplanta-
tion outcome, but interventions must not harm other potentially trans-
plantable grafts. Several donor pretreatment strategies have provided
encouraging results in animal models, but evidence from human studies
is sparse, as most clinical evidence is derived from single-center or non-
randomized trials. Furthermore, ethical matters have to be considered
especially concerning consent from donors, donor families, and trans-
plant recipients to research in the field of donor treatment. This review
provides an overview of clinically proven and promising preclinical
strategies of donor treatment to optimize long-term results after kidney
transplantation.

Transplant International 2016; 29: 974–984

Key words
brain death, donor management, kidney transplantation, organ preservation

Received: 4 June 2015; Revision requested: 2 July 2015; Accepted: 30 October 2015

or donors aged 50–59 years with two of the following

Introduction
Kidney transplantation is the treatment of choice in
end-stage renal disease, being superior to dialysis
regarding life expectation and treatment cost [1–3].
Advances in donor management, standardized surgical
techniques and improved immunosuppression have
contributed to enhanced survival rates in the last dec-
ades. Due to the enormous organ shortage, an aug-
mented use of extended criteria donors (ECD) is
needed. ECDs refer to kidney donors aged >60 years
three features: history of hypertension, serum crea-
tinine >1.5 mg/dl, or death from cerebrovascular acci-
dent. The majority of organs are retrieved from
donors after brain death (DBD), yet the unphysiologi-
cal state of brain death (BD) with metabolic, hemody-
namic, and pro-inflammatory changes is associated
with impaired graft quality, increased immunogenicity,
and compromised patient and graft survival [4,5].
Therefore, optimized care of DBDs is fundamental to
maximize the quantity, functional quality and viability

974 ª 2015 Steunstichting ESOT

doi:10.1111/tri.12712

of retrievable organs [6]. Improving care for the
potential donor already on the intensive care unit
(ICU) has the potential to attenuate irreversible harm
to the graft [7]. As organs from ECDs are more prone
to delayed graft function (DGF) and have a higher
incidence of immune-mediated rejection, optimized
donor management is of crucial importance [8]. Speci-
fic strategies solely for graft protection can only be
instituted after death and only with given consent for
donation. In line with the danger hypothesis, this
would attenuate the vicious circle of injury and
increased immunogenicity after transplantation [8].
Experimental studies highlight the benefits of this
approach, but well designed clinical trials studying
donor pretreatment are sparse [9]. Trials should ide-
ally assess the results of kidney transplantation by
hard outcome data such as patient and graft survival,
but can also consider early parameters such as DGF,
biopsy-proven acute rejection (BPAR), and evolution
of graft function. Here, we discuss current evidence of
specific donor management and organ preservation
strategies to improve these outcome parameters after
kidney transplantation.
Ethical issues of donor research
The potential of improving donor management is com-
plicated by a myriad of logistical and ethical challenges.
First, consent to donor research is unique, as interven-
tion trials include donors, donor families, and organ
recipients, but official guidelines for consent in donor-
based research are missing [10]. Donor research cannot
truly harm the deceased and donor0 s consent is not leg-
ally required, but some ethic guidelines propose the
family to give informed consent [11] while others
demand a surrogate informed consent for participation
in clinical trials [12]. Others consider the consent from
the donor family as standard to minimize the family’s
emotional distress and to maintain public trust in the
medical profession [13]. In general, it can be assumed
that donors and donor families consent to any reason-
able scientific effort to improve the outcome of donated
organs. Second, if donor research could pose a risk to
the recipient, recipient consent depends on the inter-
vention-related risks, ranging from absent to high par-
ticularly when investigational drugs or devices are used.
If required, consent for donor research should ideally
start when patients join the waiting list within the con-
text of an institutionally approved protocol for any clin-
ical trial. Due to the numerous potential interventions
and transplant centers involved in different countries,
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Donor management and organ preservation
this approach is almost unfeasible. Furthermore, trans-
plantations are unpredictable and some recipients
remain unknown even after organ procurement. The
logistical obstacles are further underlined by the need to
proceed quickly with the transplant procedure and the
fact that donor treatment should not affect allocation
[13].
Hence, the establishment of institutional review
boards and ethic committees with specialist transplanta-
tion expertise is advisable to determine the consent pro-
cess subject to the risk of intervention and to decide
whether the recipient needs to give informed consent
[9]. Additionally, a safety monitoring board is reason-
able, as it can guard each study subject enrolled within
the clinical trial [14].
Management strategies prior to organ retrieval
Antioxidant agents
Use of recombinant human superoxide dismutase (rh-SOD)
Throughout the transplantation course, kidneys are
prone to oxidative stress by multiple pre- and post-
transplant conditions, that is organ procurement, cold
preservation, and ischemia reperfusion [15]. Via acti-
vation of signaling molecules, such as nuclear factor-
kappa B, oxidative stress promotes inflammation
through the release of reactive oxygen species [16–18].
Rh-SOD is capable of scavenging free oxygen radicals
thereby minimizing oxidative stress. About 200 mg rh-
SOD given at reperfusion did not affect DGF or
recovery of graft function, but significantly reduced
the total number of acute rejection episodes (32/33.3%
of 96 controls vs. 15/18.5% of 81 rh-SOD; P < 0.027)
and severe acute rejections resulting in graft loss (12/
12.5% of controls vs. 3/3.7% of rh-SOD; P < 0.038).
Treatment with rh-SOD also improved 4-year graft
survival to 74% compared with 52% in controls. The
authors hypothesized that protection of endothelial
cells from early reperfusion injury would mitigate the
process of “chronic obliterative rejection arteriosclero-
sis” translating in improved long-term graft survival
[19,20].
Donor pretreatment with N-acetylcysteine
Antioxidant molecules are proposed to limit renal ische-
mia-reperfusion injury, but so far clinical studies con-
sidering donor treatment with these agents are rare.
Recently, an open-label monocentre trial with 160
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DBDs failed to show a beneficial effect of N-acetylcys-
teine pretreatment. N-acetylcysteine neither affected
incidence or duration of DGF nor one-year graft sur-
vival [21].
Hormonal resuscitation to antagonize unphysiological
effects after BD
BD is associated with severe hormonal alterations
resulting from failure of the pituitary gland [22]. Conse-
quently, the levels of adrenocorticotropic hormone, cor-
tisol, vasopressin, insulin, and triiodothyronine
suddenly drop after the occurrence of BD. Different
studies have replaced these hormonal deficits.
Blood sugar control and insulin
Today most organ donors have received insulin therapy
already before BD, because monitoring of blood glucose
and insulin therapy is well established in ICUs [23,24].
Current guidelines recommend target glucose levels of
180 mg/dl (9.9 mmol/l) in the critically ill [25], which
were shown to be safer than lower targets [26,27]. A
prospective study from the USA indicated that glucose
levels above 180 mg/dl are associated with lower organ
transplantation rates per donor and worsened graft out-
comes. Therefore, targeting glucose levels of ≤180 mg/dl
should be included as a management goal in potential
organ donors [28].
Administration of thyroid hormones
Retrospective studies suggest that hormonal resuscita-
tion including triiodothyronine/L-thyroxine could be
advantageous due to improvements of cardiocirculatory
function with less inotropic requirements [29–31]. Nev-
ertheless, controlled clinical data and pooled analyses on
thyroid hormone administration did not confirm a
reduced requirement of vasoactive agents, a gain in car-
diac output or an increase in the number of organs pro-
cured [32,33]. In addition, post-transplant kidney
function was not improved [34,35]. Presumably, low
triiodothyronine levels after BD reflect severe injury
rather than a hypothyroid state [32].
Administration of methylprednisolone
As endogenous cortisol levels decrease early during BD,
their supplementation is advocated because their anti-
inflammatory properties might reduce the immunologic
activation after BD [36]. In experimental transplanta-
976
tion, steroid use decreased immune-mediated attack
and improved graft function [37,38]. However, these
findings could not be confirmed in humans, as early
studies failed to show an advantageous effect of donor
treatment with methylprednisolone [39–43]. Few smal-
ler studies on combined use of cyclophosphamide and
methylprednisolone also suggested improved 5-year
graft survival [40,41], but could not be confirmed by
others [42,43].
Recently, a large randomized double-blind trial (269
DBDs) was conducted to investigate the effects of
methylprednisolone pretreatment in kidney transplanta-
tion. About 1000 mg methylprednisolone 3 h before
organ retrieval significantly ameliorated gene expression
profiles of inflammatory and apoptotic transcripts but
had no effect on incidence and duration of DGF, or
decline of serum creatinine during the first week.
Hence, high-dose methylprednosolone before organ
retrieval is not recommended at least in kidney trans-
plantation [36]. It was argued that the negative result of
the study was due to the very short time window
between study intervention and initiation of cold
preservation. Nevertheless, preliminary data suggest that
donor treatment with steroids might be beneficial in
liver and lung transplantation [44–46]. As retrospective
registry-based data indicate that hormonal resuscitation
including methylprednisolone increases the yield of
transplantable organs per donor, the routine use of ster-
oids as part of a combined hormonal resuscitation has
to be discussed.
Administration of low-dose dopamine
As a consequence of BD, sympathetic outflow is inter-
rupted and vasodilatation occurs, leading to hemody-
namic instability, so that 80–90% of all DBDs need
vasoactive support to maintain adequate organ perfu-
sion. Expert opinions differ, which adrenergic agent
should be administered first-line, as clinical studies on
use of adrenergic agents focusing on graft outcome are
sparse and produced conflicting results [47].
Dopamine has traditionally been first choice for
donors with hemodynamic instability [48], but one ret-
rospective study linked the use of dopamine to an
increased incidence of DGF. Yet, in-depth analysis
revealed that this association was presumably con-
founded by severe hypotension periods in these donors
[49]. Another retrospective study concluded that use of
vasopressors reduced the likelihood of immediate allo-
graft function [50]. This was confirmed by a prospective
cohort study indicating that donor inotropic support is
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associated with less immediate graft function and
poorer renal graft survival [51]. In contrast, a Canadian
study identified no dopamine use as a determinant of
initial nonfunction in a multivariate analysis and rec-
ommended low-dose therapy for all donors [52]. An
intriguing finding from our center was, that donor
dopamine and to a lesser extent norepinephrine were
associated with less acute rejection after kidney trans-
plantation and translated in improved graft survival
[53]. A benefit was also shown in a large multicenter
cohort study of 2415 kidney transplants from 1993 indi-
cating that adrenergic agents improved 4-year graft sur-
vival in an apparently dose-dependent manner [54].
Like in the Canadian study, donor dopamine was also
associated with reduced dialysis requirements after
transplantation, whereas norepinephrine was not [55].
Based on these data, a multicenter randomized con-
trolled trial was initiated in 2004, which confirmed that
treatment of DBDs with low-dose dopamine (4 lg/kg/
min) improves immediate graft function after kidney
transplantation. The beneficial effect was enhanced for
kidney grafts with prolonged cold ischemic time (CIT)
exceeding 17 h and translated in improved graft survival
in this subgroup. Donor dopamine only infrequently
induced adverse events, namely tachycardia (10.0%) and
hypertension (3.3%), that were reversible after dose
reduction or premature termination of the dopamine
infusion [56].
Molecular mechanism of dopamine
The advantageous effects of dopamine were not medi-
ated through hemodynamic stabilization, because all
donors were similar with respect to blood pressure and
urine production. Protection is believed to result from
the antioxidant properties of the dopamine molecule
[57]. Cellular damage following prolonged CIT is in part
ascribed to oxidative stress. Under cold storage condi-
tions, accumulation of reactive oxygen species (ROS)
leads to an increased release of calcium ions [58]. A
vicious circle is activated, as intracellular calcium home-
ostasis depends on high energy phosphates which main-
tain the mitochondrial membrane potential. While
synthesis of ATP is decreased under hypothermia, the
influx of calcium further exhausts ATP. Abundant intra-
cellular calcium aggravates mitochondrial damage, with
the consequence that the mitochondrial membrane
potential ultimately breaks down [59]. We have demon-
strated that dopamine decelerates the deleterious ampli-
fication loop of intracellular calcium accumulation and
subsequent ATP consumption by scavenging of ROS
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Donor management and organ preservation
[60,61]. In addition, it was shown that dopamine also
increases H2S-production by stimulating endogenous
cystathionine-b-synthase, which protects cells from
ROS-formation and apoptosis after cold storage upon
rewarming [62].
Administration of desmopressin (1-deamino-8-D-arginine-
vasopressin [DDAVP])
About 80–90% of all DBDs develop central diabetes
insipidus with profuse polyuria and potentially severe
dehydration. DDAVP promotes fluid re-absorption in
the collecting duct and decreases the need for large vol-
ume infusions to hemodynamically stabilize the DBD
[63]. Early studies with DDAVP did not show any
favorable effect on recipients’ outcome after transplanta-
tion [64,65]. However, in a more recent study, renal
transplant recipients from DDAVP treated donors
showed less rejections episodes and lower serum crea-
tinine values 1 and 3 years after transplantation [66].
The retrospective analysis of the dopamine multicenter
trial confirmed this observation. While DDAVP pre-
treatment had no effect on short-term outcome such as
DGF, BPAR, or decline of serum creatinine during the
first week post-transplant, it was significantly associated
with improved 2-year graft survival (85.4% vs. 73.6%,
log-rank P = 0.003). Subgroup analyses indicated that
DDAVP was only beneficial if cold storage was short
(below 14 h) or the donor was assigned to dopamine
pretreatment. Exposure to hypoxia during cold preser-
vation and shear stress during reperfusion induces exo-
cytosis of Weibel-Palade bodies (WPB) releasing various
pro-inflammatory cytokines. Both a shorter CIT and
dopamine protect the graft’s endothelium from cold
storage injury. It was hypothesized that DDAVP treat-
ment deprives WPB from the intact endothelium of the
graft before its exposure to ischemia/reperfusion injury.
Reduced release of pro-inflammatory cytokines during
transplantation may attenuate inflammation and trans-
plant vasculopathy.
Combined hormonal resuscitation
In a retrospective analysis of the UNOS database, com-
bined therapy with methylprednisolone, vasopressin,
and triiodothyronine/L-thyroxine as “hormonal resusci-
tation” raised organ yield per donor, especially kidneys
by 7.3% [67] and was associated with improved kidney
graft survival after 1 year [68]. As it is impossible to
define the role of any single agent, optimal hormonal
replacement therapy in DBDs yet remains to be estab-
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Mundt et al.
Table 1. Overview of hormonal replacement and
vasopressor use in organ donors.
Hormone/Treatment Recommendation for administration
Insulin for blood Achieve glucose levels of ≤180 mg/dl
sugar control [28]
Thyroid hormones Not recommended as a single agent
Increases number of transplantable
organs per donor within general
“hormonal resuscitation” [67]
Methylprednisolone General consideration
Potential benefit in liver and lung
transplantation [44–46]
Increases number of transplantable
organs per donor within general
“hormonal resuscitation” [67]
DDAVP Brain death induced diabetes insipidus
(diuresis >5 ml/kg/hr with specific
gravity <1005 mg/ml)
Might improve kidney graft survival
[69]
Potentially fewer acute rejections
and improved creatinine [66]
Vasopressors Kidney donors: Low-dose dopamine
(4 lg/kg/min)
Reduction of DGF [56]
Improved survival if CIT >17 h [56]
lished. Table 1 gives an overview of clinically proven
therapies from hormonal resuscitation trials.
Fluid replacement therapy
Hypovolemia with circulatory collapse is a frequent
complication in DBDs due to central diabetes insipidus,
and loss of sympathetic tone [63]. Hence, adequate fluid
replacement is essential to prevent acute renal failure.
Crystalloid solutions such as 0.9% saline or Ringer’s lac-
tate are considered first choice because they have no
specific side effects, but may rarely increase edema forma-
tion. Balanced crystalloid solutions are preferable particu-
larly if resuscitation of larger fluid volumes is required,
because administration of 0.9% saline may cause hyper-
chloremic metabolic acidosis [7]. Crystalloid fluid load-
ing to a CVP of 8–10 mmHg may be deleterious to lung
function and should be avoided in potential lung donors
[70]. Colloid solutions could be an alternative to avoid
interstitial fluid overload, but they are associated with a
significant risk of anaphylactic reactions. Furthermore,
HES (hydroxyl ethyl starch) should be avoided in kidney
donors, because osmotic nephrosis-like lesions were
detected in transplanted kidneys after HES treatment
[71], which were associated with elevated creatinine levels
978
in the recipients [72]. However, these findings were not
confirmed by others [73]. Due to competing interests
regarding optimal treatment of multi-organ donors, lung
surgeons would perhaps prefer colloid solutions to stabi-
lize circulation, as gas exchange might be improved by
attenuation of neurogenic pulmonary edema. Neverthe-
less, evidence so far has linked HES to an increased risk of
death and renal-replacement therapy in ICUs; therefore,
use of HES is discouraged [74,75] (Table 2).
General donor management goals (DMG)
International procurement organizations have adopted
critical care endpoints as management goals for donor
treatment after confirmation of BD. This resulted in an
increased organ yield as shown by various retrospective
analyses [77,78]. Recently, a prospective evaluation by
UNOS revealed that a limited number of donors only
achieve target criteria, but efforts to meet DMG are
associated with significantly higher rates of trans-
plantable organs per donor [79] (Table 3). In addition,
DGF after kidney transplantation was less common
when DMG were met (17% vs. 30%; P = 0.007) [80]
indicating that optimized care for DBDs will not only
extend the pool of organs but also improve clinical out-
come after transplantation.
Therapeutic hypothermia in deceased organ donors
Therapeutic hypothermia has been shown to be a bene-
ficial intervention to protect neurologic function of
patients with specific types of cardiac arrest or stroke
[81–83]. Recently, a large prospective trial in deceased
organ donors (n = 370) showed that mild hypothermia
(34–35 °C) significantly reduced the rate of DGF among
recipients (28% vs. 39%, odds ratio 0.62; P = 0.02)
[84]. Subgroup analysis showed that high-risk donors,
such as ECDs, particularly benefited from hypothermia
(odds ratio 0.31; 95% CI 0.15–0.68; P = 0.003).
Organ storage: Static cold storage or
hypothermic machine perfusion (MP)
Transplants from ECDs are more susceptible to cold
storage inflicted injury, which causes higher rates of
DGF and increases the risk for graft failure [85,86].
Therefore, optimizing organ preservation to maintain
organ quality is a crucial factor for transplantation suc-
cess. Although static cold preservation is used for the
majority of organs transplanted [87,88], MP might be
more appropriate to maintain graft viability, especially
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 Donor management and organ preservation

if organs are retrieved from ECDs or donors after car- (91% vs. 87%; P = 0.04) with MP. Interestingly, the
diac death (DCD) [89]. Early retrospective data indicate benefit of MP could be detected in the subgroup of
that MP may reduce DGF and result in a mild benefit DBDs only (91% vs. 86%; P = 0.02), being pronounced
on death-censored graft survival [90,91]. Another retro- in the subgroup of ECDs (86% vs. 76%; P = 0.01) but
spective study including 912 renal allografts revealed not in DCDs [94]. The suggested beneficial effect for
similar results considering DGF, albeit graft survival ECDs could also be shown in 85 ECD kidneys allocated
remained unaffected [92]. in the Eurotransplant Senior Program. MP reduced the
These initial studies were followed by a large prospec- rate of PNF and improved 1-year graft survival of kid-
tive multicenter trial assessing the influence of MP on neys suffering from DGF, however, no benefit on the
DGF [93]. In this study, one kidney of each donor was incidence of DGF was found, possibly due to the short
randomly assigned to MP or to static cold preservation. CIT of 11 h [95]. However, the above study [93,94] has
MP significantly reduced the rate of DGF (20.8% vs. been criticized, as MP reduced DGF only slightly from
26.5%; P = 0.05) and numerically halved primary non- 89/336 to 70/336, that is, a prevention of 19 episodes in
function (PNF) (2.1% vs. 4.8%; P = 0.08). Duration of 336 transplantations (= 5.7%) and may thus not explain
hospital stay and BPAR were unaffected, but MP signifi- a 4% difference in graft survival. Furthermore, in 25
cantly improved 1-year graft survival (94% vs. 90%, donors assigned to MP in whom vascular anatomy was
P = 0.04). The beneficial effect of MP was similar for considered unsuitable the contralateral kidneys was used
standard criteria and for ECDs. Recently, 3-year follow- instead. These kidney pairs were not excluded but ana-
up data indicated superior long-term graft survival lyzed according to the actual preservation technique
and not “intention to treat”. This ambiguous assign-
ment resulted in a higher number of kidneys with vas-
Table 2. Overview of reported risks and disadvantages of cular abnormalities in controls. Also, MP failed in seven
crystalloid and colloid solutions in potential multi-organ
instances. These kidney pairs were excluded from analy-
donors.
sis, although they were transplanted. Failure of the
Crystalloid solutions Colloid solutions pump could have increased DGF risk and exclusion of
Increase of neurogenic Risk of anaphylactic reactions these kidneys might bias results in favor of MP. There-
pulmonary edema in fore, the value of MP in kidney transplantation is still a
potential lung donors matter of debate, also because other studies could not
[70,76] confirm these findings.
Edema formation Induction of osmotic nephrosis-like
The UK multicenter trial which randomly assigned
lesions [71]
Increased risk of death and DCD kidneys either to MP or static cold storage failed to
renal-replacement therapy show any effect on DGF (58% vs. 56%; P = 0.99). Sur-
in ICUs [74,75] prisingly, MP was associated with an increased rate of
BPAR in the first 3 months (22% vs. 7%; P = 0.06), but
this did not influence graft or patient survival after
12 months [96]. Also, MP was associated with lower graft
Table 3. Recommended donor management goals to
raise organ yield per donor, adapted from [79]. survival in a large registry-based study (n = 2202), even
when the analyses were stratified for duration of CIT [87].
United Network for Organ Sharing (UNOS) region 5 donor
Finally, several meta-analyses have been performed to
management goals
summarize the available evidence on MP in different
Central venous pressure 4–10 mmHg
donor types. A meta-analysis including all donor types
Ejection fraction >50% revealed that MP reduced DGF rates, but had no influence
Vasopressors ≤1 and low dose* on PNF, acute rejections, and graft or patient survival
Arterial blood gas pH 7.3–7.45 [97]. Subsequent meta-analyses were restricted to DCDs
PaO2:FiO2 >300 and found that MP reduced DGF, but the incidence of
Serum sodium 135–155 mmol/l
PNF and 1-year graft or patient survival was unaffected
Blood glucose <150 mg/dl
Urine output 0.5–3 ml/kg/h over 4 h [98,99]. Another meta-analysis considering ECDs only
Mean arterial pressure 60–100 mmHg (2374 MP vs. 8716 CS) concluded that MP was superior in
preventing DGF, and increased 1-year graft survival, how-
*Dopamine ≤10 lg/kg/min, phenylephrine ≤60 lg/kg/min,
ever did not affect PNF or patient survival [100]. Meta-
and norepinephrine ≤10 lg/kg/min.
analysis is limited due to study heterogeneity in terms of
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Mundt et al.
the pump systems, perfusion pressures, and cold storage
solutions examined [100]. In summary, the available evi-
dence about the use of MP is controversial [101]. The use
of MP may prove to be beneficial in high-risk grafts from
ECDs or after prolonged CIT [85].
Preclinical and experimental donor treatment
strategies
Ischemic preconditioning (IPC)
Remote IPC is one potential approach to protect kid-
neys from ischemia-reperfusion injury. Although the
underlying mechanism needs to be fully defined [102],
the concept of IPC was shown to be beneficial in rodent
models of kidney transplantation [103–106], but large
animal models failed to confirm these results [107,108].
Furthermore, remote IPC by occluding the thigh (three
times for 5 min, either in donors or recipients) failed to
improve renal function within 72 h after human living
donor transplantation [109]. Nonetheless, patients are
currently recruited into an interventional randomized
trial to investigate the effect of remote IPC on immedi-
ate and 1-year graft function (NCT01395719) [9].
Vagus nerve stimulation
Electric stimulation of the vagal nerve in a BD rodent
decreased transcription of pro-inflammatory genes,
reduced monocyte infiltration of the graft, and improved
its function after transplantation [110]. The mechanism
of action is presumably related to restoring vagus nerve
activity, resulting in recovery of the anti-inflammatory
reflex. Recently, also a long-term benefit with less chronic
allograft nephropathy (CAN) was shown [111].
Atorvastatin
In an isogeneic transplantation model, atorvastatin pre-
vented ischemia-reperfusion injury and improved renal
function [112]. Atorvastatin may be beneficial by
inhibiting aldose reductase, which plays a major role in
oxidative stress [113–115], but the benefit of statin
treatment could not be shown in animal transplantation
models after BD induction [116].
Erythropoietin
High-dose erythropoietin provides anti-apoptotic and
cytoprotective effects and might enhance the graft’s resis-
tance to ischemic injury after BD. In a rat model, erythropoi-
980
etin diminished the expression of pro-inflammatory genes,
decreased the infiltration of polymorphonuclear cells and
restored kidney function after BD [117]. In a large animal
model of donor pigs erythropoietin decreased renal injury,
inflammation and improved kidney function after transplan-
tation [118]. Nevertheless, clinical studies using erythropoi-
etin before surgery and/or following transplantation had no
beneficial effect on graft outcome [119,120]. In one trial,
administration of erythropoietin even increased the risk of
thrombotic events 1 year after transplantation [121].
Carbon monoxide (CO)
Upcoming evidence suggests that application of carbon
monoxide in DBDs is another promising approach for
prevention of ischemia-reperfusion injury [122]. Addition-
ally, it was demonstrated in rat transplant models that CO is
capable of diminishing the graft’s immunogenicity, that is
donor-derived dendritic cells already before transplantation
[122–124]. Furthermore, CO was shown to inhibit CAN
and to improve survival even when the treatment is started
after diagnosis of CAN [125]. The promising role of CO in
transplantation is reviewed in detail elsewhere [126,127].
Conclusion
As a consequence of organ shortage, grafts from ECDs
need to be used to supply the demand of transplantable
organs. Grafts from ECDs are more susceptible to vari-
Table 4. Human randomized controlled trials of donor
management showing a beneficial effect after kidney
transplantation.
Effect on outcome after
Specific donor treatment kidney transplantation
Glucose levels of <180 mg/dl Higher organ transplantation
rate per donor [28]
Meeting donor management Higher rate of transplantable
goals organs per donor [79]
Reduction of DGF [80]
Low-dose dopamine Reduction of DGF [56]
(4 lg/kg/min)
Human superoxide Reduced number of acute
dismutase (rh-SOD) rejections, improved 4-year
graft survival [19]
Hypothermic machine Reduced rate of DGF,
perfusion Improved 1- and 3-year graft
survival, especially for ECDs
[93,94]
Therapeutic hypothermia Reduction of DGF, especially
for ECDs [84]
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 Donor management and organ preservation

ous deleterious events occurring during the course of
transplantation. To preserve graft viability, optimized
donor management is increasingly important. Several
(pre) clinical donor treatment strategies have revealed
promising results, demonstrating the great potential of
specific interventions in the DBD.
According to the available evidence, donor manage-
ment goals have been elaborated to increase organ yield
per donor. Regarding specific interventions, randomized
controlled trials indicate that donor pretreatment with
low-dose dopamine or the administration of human
superoxide dismutase at time of reperfusion improve
the outcome after kidney transplantation by scavenging
of ROS. Additionally, as recently shown, mild hypother-
mia lowers the rate of DGF among recipients, especially
in high-risk donors like ECDs. While optimal organ
storage is still a matter of debate, current data suggest a
beneficial effect by hypothermic machine perfusion,
especially for ECDs (Table 4).
In general, overall clinical evidence of donor interven-
tions on graft outcome is sparse and mostly lacks long-
term results. Important additional issues comprise com-
peting interests of some organ-specific interventions [on
quality and procurement of other organs from the same
donor] and ethical considerations, that is informed con-
sent from donors and recipients with regard to trials in
donor management. Current donation and allocation sys-
tems should incorporate donor management protocols to
optimize results for transplant recipients and be better
designed to facilitate further research that can improve
the utility of this most precious resource.
Funding
The authors have declared no funding.
Conflicts of interest
All authors declare that they do not have any conflict of
interest with this publication.

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ª 2015 Steunstichting ESOT